The endogenous cholinergic neurotransmitter, acetylcholine (ACh), exerts its biological effect via two types of cholinergic receptors: the muscarinic ACh receptors and the nicotinic acetylcholine receptors (nAChRs). Because muscarinic ACh receptors dominate quantitatively over nAChRs in the brain area important to memory and cognition, much research aimed at the development of agents for the treatment of memory related disorders have focused on the synthesis of muscarinic ACh receptor ligands. Recently, however, an interest in the development of nAChR ligands has emerged.
Several diseases are associated with degeneration of the cholinergic system, such as senile dementia of the Alzheimer's type, vascular dementia and cognitive impairment due to the organic brain damage disease related directly to alcoholism. Indeed, several CNS disorders can be attributed to a cholinergic deficiency, a dopaminergic deficiency, an adrenergic deficiency or a serotonergic deficiency. Alzheimer's disease is characterized by a profound loss of memory and cognitive functions caused by a severe depletion of cholinergic neurons, i.e., neurons that release acetylcholine. A reduction in the number of nAChRs are also observed with the progression of Alzheimer's disease (Whitehouse P J et al. (1986) Nicotinic acetylcholine binding sites in Alzheimer's disease. Brain Research 371(1):146-151). It is predicted that treatment of Alzheimer patients with nAChR ligands will not only improve the memory of patients but in addition act to keep these neurons alive.
However degeneration of the cholinergic system is not limited to individuals suffering from, for example, Alzheimer's disease but is also seen in healthy aged adults and rats. Therefore it is suggested that the cholinergic system is involved and partly responsible for the memory disturbances seen in aged animals and humans. Nicotinic receptor ligand may therefore be useful in the treatment of Alzheimer's disease, memory loss, memory dysfunction, AIDS-dementia, senile dementia or neurodegenerative disorders.
Parkinson's disease appears to involve degeneration of dopaminergic neurons. One symptom of the disease has been observed to be loss of nAChRs associated with the dopaminergic neurons and possibly interfering with the process of release of dopamine. As sustained nicotine administration increases the number of receptors present, administration of nAChR ligands may ameliorate the symptoms of Parkinson's disease. Other condition or disorders or disease ascribed to deficiencies in the dopaminergic system is: drug addiction, depression, obesity and narcolepsy.
Tourette's syndrome is a neuropsychiatric disorder involving a range of neurological and behavioral symptoms. It is believed that neurotransmitter dysfunction is involved though the pathophysiology is still unknown and that nicotine will be beneficial in the treatment of the disease (Devor et. al. The Lancet, vol. 8670 p. 1046, 1989).
Schizophrenia is a severe psychiatric illness. Neuroleptic compounds have been used in the treatment of the disease; the effect of the compounds is believed to be based on interactions in the dopaminergic system. Nicotine is proposed to be effective in the treatment of schizophrenia (Merriam et. al. Psychiatr. Annals, Vol. 23, p. 171-178, 1993 and Adler et. al. Biol. Psychiatry, Vol. 32, p. 607-616, 1992.)
Nicotine has been reported to have en effect on neurotransmitter release in several systems. Release of acetylcholine and dopamine by neurons upon administration of nicotine has been reported (J. Neurochem. vol. 43, 1593-1598, 1984) and release of norepinephrine by Hall et. al. (Biochem. Pharmacol. vol. 21, 1829-1838, 1972), release of serotonin by Hery et. al. (Arch. Int. Pharmacodyn. Ther. vol. 296. p. 91-97, 1977). and release of glutamate by Toth et. al (Neurochem. Res. vol. 17, p. 265-271, 1992) have also been reported.
The serotonin system and dysfunction's of the serotonergic system is believed to be involved in diseases or conditions or disorders like: anxiety, depression, eating disorders, obsessive compulsive disorder, panic disorders, chemical substance abuse, alcoholism, pain, memory deficits and anxiety, pseudodementia, Ganser's syndrome, migraine pain, bulimia, obesity, pre-menstrual syndrome or late luteal phase syndrome, tobacco abuse, post-traumatic syndrome, social phobia, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, disorders of sleep, autism, mutism and trichotillomania.
Nicotine improves concentration and task performance. Therefore compounds exhibiting nAChR modulating properties will be likely to be useful compounds in the treatment of learning deficit, cognition deficit, attention deficit, attention deficit hyperactivity disorder and dyslexia.
Tobacco use and especially cigarette smoking is recognized as a serious health problem. However nicotine withdrawal symptoms associated with smoking cessation makes it difficult to break this habit. Withdrawal symptoms include anger, anxiety, difficulties in concentrating, restlessness, decreased heart rate and increased appetite and weight gain. Nicotine itself has shown to ease the withdrawal symptoms.
Withdrawal from addictive substances, such as opiates, benzodiazepines, ethanol, tobacco or nicotine, is in general a traumatic experience characterized by anxiety and frustration. Nicotine has been found to be effective in reducing anger, irritability, frustration and feelings of tension without causing general response depression, drowsiness or sedation and compounds targeting nAChRs is likely to have same effects.
Mild to moderate pain is typically treatable with NSAIDs (non-steroidal anti-inflammatory drugs), while opiates are used preferentially for moderate to severe pain. The opiates have some well-known side-effects, including chemical dependence and abuse potential, as well as a depressive effect on the respiratory and gastrointestinal system. There exists, therefore, a pressing need for analgesic compounds that do not exhibit these side effects and which can relieve mild, moderate and severe pain of acute, chronic or recurrent character, as well as migraine pain, postoperative pain, and phantom limb pain.
Epibatidine, a compound isolated from the skin of a poison frog, is a very potent analgesic with an approximate potency of 200 times that of morphine. The analgesic effect is not affected by naloxone, which is an indication of a negligible affinity for the opiate receptors. Epibatidine is an nAChR agonist and it is therefore very likely, that compounds possessing this receptor modulating character will also show a strong analgesic response. It is well known that nicotine has an effect on appetite and it is predicted that ligands at the nicotine ACh receptor may be useful as appetite suppressants in the treatment of obesity and eating disorders.
In addition to epibatidine, various heterocyclic 2-pyrrolidinyloxy-substituted compounds with analgesic and hypotensive activities have been disclosed by Scheffler et al. (U.S. Pat. No. 4,643,995) and Tomioka et al. (Chem. Pharm. Bull, 38:2133-5, 1990).
Certain other 2-pyridyloxy-substituted compounds are disclosed inter alia by Engel et al. in U.S. Pat. No. 4,946,836 as having analgesic activity.
Various other compounds having a pyrrolidine or azetidine moiety substituted at the 3-position with a heterocycloxy group have also been disclosed (see, for example, U.S. Pat. No. 4,592,866 to A. D. Cale; U.S. Pat. No. 4,705,853 to A. D. Cale; U.S. Pat. No. 4,956,359 to Taylor et al.; U.S. Pat. No. 5,037,841 to Schoehe et al.; US Pat. App. Pub. No. 2008/0132486 to Kozikowski et al; PCT Patent App. Pub. No. WO 2008/011484 A2 to Xiao et al; and European Pat. App. No. EP296560 A2 to Sugimoto et al).
The cholinergic receptors play an important role in the functioning of muscles, organs and generally in the central nervous system. There are also complex interactions between cholinergic receptors and the function of receptors of other neurotransmitters such as dopamine, serotonin and noradrenaline.